Opioids, such as morphine, codeine, hydromorphone, hydrocodone, oxymorphone, and oxycodone, are important analgesics. Their dihydro-reduction products, the 6-hydroxy analogs such as 6α-hydromorphol, 6α-hydrocodol, 6α-oxymorphol, and 6α-oxycodol, also have analgesic effects along with other beneficial characteristics. Recently, polymer-functionalized 6-hydroxy opioid compounds have been reported to have sustained-release and abuse-resistant properties in addition to their common opioid analgesic effects. Patient enrollment for a Phase II clinical trial of PEGylated 6α-oxycodol is currently underway.
Producing hydroxy opioid compounds, however, generally proceeds through a number of steps, where each step requires isolation of the intermediate before the next synthetic step can be performed. For example, 6α-oxycodol can be prepared by reducing oxycodone, which itself was prepared from thebaine by oxidation followed by reduction, thus requiring three isolation steps. Isolation becomes necessary for a number of reasons, including the interference of reaction byproducts with later steps, which may lower the yield or halt the reaction altogether. But, isolation of intermediates itself is an extra step that can lower the yield and efficiency of the total synthesis. Thus, there is a need to develop a high yielding one-pot process for the multiple reaction steps in order to simplify operations so that production cost and cycle time may be reduced.